Tremendous effort has been made during the last decades to develop novel supports to facilitate organic synthesis. These supports have been used not only to carry out multi-step organic synthesis of organic molecules (Horton, D. A.; Bourne, G. T.; Smythe, M. L., Chem. Rev. 2003, 103, 893-930; and Benaglia, M.; Puglisi, A.; Cozzi, F., Chem. Rev. 2003, 3401-3429) but also to bind catalysts, reagents and scavengers to facilitate the purification process of a product or to facilitate the recovery of a potentially expensive catalyst or reagent (Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew. Chem. Int. Ed. 2001, 40, 650-679). Various strategies that have been used are detailed within the next paragraphs.
A first approach initiated by Merrifield (Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149) was to use functionalized cross-linked, insoluble polymers. This solid-phase technology revolutionized the polypeptide and polynucleotide synthesis and was soon employed to develop solid-supported reagents and catalysts (Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K., Synthesis 1997, 1217-1239; Bhalay, G.; Dunstan, A.; Glen, A., Synthesis 2000, 1846-1859). The main advantages of this solid-phase methodology are the ease of separation of the supported species from the reaction mixture and the high loadings allowed in the preparation of the functionalized polymer. However, the major drawback is the lower reactivity of the solid-supported reagent compared to that observed for the corresponding homogeneous reaction because of limited diffusion of the substrate into the polymer backbone. Therefore, an excess of reagent or scavenger must usually be used to force the reaction to completion. Furthermore, the synthesis of the functionalized polymer may be sometimes troublesome since reactive functionality has to be introduced on the polymer backbone.
Silica bound scavengers or reagents have been developed (Heckel, A.; Seebach, D. Angew. Chem. Int. Ed. 2000, 39, 163-165). The silica rigid and non-swelling backbone eliminates solvent compatibility and kinetic issues. Nevertheless these reagents are more difficult to produce due to loading control issue and the difficulty in characterizing the silica gel once prepared.
As an attempt to restore the classical homogeneous organic chemistry conditions, the replacement of insoluble resins by a soluble polymer support became a popular modification (Dickerson, T. J.; Reed, N. N.; Janda, K. D., Chem. Rev. 2002, 102, 3325-3344; and Bergbreiter, D. E., Chem. Rev. 2002, 102, 3345-3384). The non-cross linked support is typically soluble is some solvents and insoluble in others. However, the difficulties associated with this solution-phase technique were to obtain a reasonable loading capacity of the reagent since higher loadings usually led to unpredictable solubility properties. The ability to isolate the polymer cleanly from all the other components at the end of a reaction can also be a problem.
Among the soluble polymers: polyethylene polyethylene glycols (PEGs) (Han, H.; Janda, K. D., J. Am. Chem. Soc. 1996, 118, 7632-7633; and Yao, Q. Angew. Chem. Int. Ed. 2000, 39, 3896-3898) and non cross-linked polystyrene (NCLP) (Enholm, E. J.; Gallagher, M. E.; Moran, K. M.; Lombardi, J. S.; Schulte II, J. P., Org. Lett. 1999, 1, 689-691; and Charette, A. B.; Boezio, A. A.; Janes, M. K., Org. Lett. 2000, 2, 3777-3779) have been by far the most widely used for the recovery and the recycling of reagent or catalyst.
A recent approach used solid-support derived from ring-opening metathesis polymerization (ROMP) (Barrett, A. G. M.; Hopkins, B. T.; Köbberling, J. Chem. Rev. 2002, 102, 3301-3324). Typically, the key transformations are conducted in solution to afford the monomer. A subsequent ring-opening metathesis polymerization using expensive ruthenium catalysts gives a polymer witch can be easily modified and optimized. Thus, the polymer could be prepared as either soluble or insoluble species. Nevertheless the functional groups compatible with the metathesis are limited and the need to precipitate selectively the polymer remains a major issues that requires extensive optimization.
A complementary approach involves linking of a catalyst or reagent on a dendrimeric structure (Ji, B. M.; Yuan, Y.; Ding, K. L.; Meng, A. B., Chem.-Eur. J. 2003, 9, 5989-5996; Lu, S. M.; Alper, H., J. Am. Chem. Soc. 2003, 125, 13126-13131; and Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H., J. Am. Chem. Soc. 2000, 122, 8168-8179). One advantage is that the catalyst can be easily recovered and potentially reused, however, the synthetic sequence to build the dendrimeric structure is most of the times quite tedious since lengthy organic reaction sequences are usually required to build up the optimal system.
Another area is the ionic liquid chemistry (Tzschucke, C. C.; Markert, C.; Bannwarth, W.; Roller, S.; Hebel, A.; Haag, R. Angew. Chem. Int. Ed. 2002, 41, 3964-4000). These liquids are prepared by alkylation of the corresponding pyridine, imidazole, amine or phosphine with an alkyl halide to form the pyridinium, imidazolium, ammonium or the phosphonium salt. Then, the desired anion is installed by ion exchange with the alkali salt or by using an ion-exchange resin. This modification allows modulation of the solubility properties and melting point of the ionic liquid. The most popular ionic liquid is the [BMIM]+[X]− (BMIM=1-n-butyl-3-methylimidazolium, X=OTf, BF4, PF6, SbF6). As ionic liquids are highly polar and non-coordinating solvent, they dissolve easily transition-metal complexes mainly without changing their properties. Thus, the principal ionic liquids application is the domain of the recoverable catalyst. The ionic liquid phase can be reused and ligands bearing an ionic group can easily be designed. However most of reactant species must be solubilize in the ionic liquid by addition of a co-solvent or by heating. At the end of a reaction, product extraction could be difficult and the catalyst could leach out of the ionic liquid into the organic layer.
The fluorous phase is another useful alternative (Curran, D. P. Angew. Chem. Int. Ed. 1998, 37, 1174-1196). Reactants and catalysts can be labeled with a certain number of fluorine atoms to stay in the fluorous phase. Perfluoro protecting groups have been developed, allowing a substrate to be temporarily tagged for its purification on a fluorous reverse-phase column or to be soluble in the fluorous phase. Even if a co-solvent or a hybrid solvent (organic solvent bearing few fluorine atoms) are added to adjust the solubility, this methodology remain somewhat specific since the molecules must bear a number of fluorine atoms.
Reagents bearing basic or acidic moieties have also been developed. The major drawback from this system comes from the presence of a relatively reactive group (acid or basic) within the reagent and they have not been used that much in synthesis.